Rhabdomyosarcoma, one of the most common childhood sarcomas, is comprised of two main subtypes, embryonal and alveolar (ARMS). ARMS, the more aggressive subtype, is primarily characterized by the t(2;13)(p35;p14) chromosomal translocation, which fuses two transcription factors, PAX3 and FOXO1 to generate the oncogenic fusion protein PAX3-FOXO1. Patients with PAX3-FOXO1-postitive tumors have a poor prognosis, in part due to the enhanced local invasive capacity of these cells, which leads to the increased metastatic potential for this tumor. Despite this knowledge, little is known about the role that the oncogenic fusion protein has in this increased invasive potential. In this report we use large-scale comparative transcriptomic analyses in physiologically relevant primary myoblasts to demonstrate that the presence of PAX3-FOXO1 is sufficient to alter the expression of 70 mRNA and 27 miRNA in a manner predicted to promote cellular invasion. In contrast the expression of PAX3 alters 60 mRNA and 23 miRNA in a manner predicted to inhibit invasion. We demonstrate that these alterations in mRNA and miRNA translate into changes in the invasive potential of primary myoblasts with PAX3-FOXO1 increasing invasion nearly 2-fold while PAX3 decreases invasion nearly 4-fold. Taken together, these results allow us to build off of previous reports and develop a more expansive molecular model by which the presence of PAX3-FOXO1 alters global gene regulatory networks to enhance the local invasiveness of cells. Further, the global nature of our observed changes highlights the fact that instead of focusing on a single-gene target, we must develop multi-faceted treatment regimens targeting multiple genes of a single oncogenic phenotype or multiple genes that target different oncogenic phenotypes for tumor progression.
Existing models of aortic stenosis (AS) are limited to inducing left ventricular pressure overload. As they have reduced control over the severity of aortic constriction, the clinical relevance of these models is largely hindered by their inability to mimic AS hemodynamics and recapitulate ow patterns associated with congenital valve defects, responsible for the accelerated onset and progression of AS. Here we report the development of a highly tunable bio-inspired soft robotic tool that enables the recapitulation of AS in a porcine model, in which customization of actuation patterns allows hemodynamic mimicry of AS and congenital aortic valve defects. In vitro and computational tools including lumped-parameter, nite element, and computational uid dynamics platforms were developed to predict the hemodynamics induced by the bio-inspired soft robotic sleeve. The controllability of our in vivo model and its ability to replicate ow patterns of AS and congenital defects were demonstrated in swine through echocardiography, left ventricular catheterization, and magnetic resonance imaging. This work supports the use of soft robotics to simulate human physiology and disease, while paving the way towards the development of patient-speci c models of AS and congenital defects that can guide clinical decisions to improve the management and treatment of these patients.
Background Late gadolinium enhancement cardiac magnetic resonance imaging is an effective and reproducible method for characterizing myocardial infarction. However, gadolinium‐based contrast agents are contraindicated in patients with acute and chronic renal insufficiency. In addition, several recent studies have noted tissue deposition of free gadolinium in patients who have undergone serial contrast‐enhanced magnetic resonance imaging. There is a clinical need for alternative forms of magnetic resonance imaging contrast agents that are acceptable in the setting of renal insufficiency. Methods and Results Three days after 80 minutes of ischemia/reperfusion of the left anterior descending coronary artery, cardiac magnetic resonance imaging was performed to assess myocardial lesion burden using both contrast agents. Late gadolinium enhancement cardiac magnetic resonance imaging was examined 10 and 15 minutes after contrast injection. Contrast agents were administered in alternating manner with a 2‐ to 3‐hour washout period between contrast agent injections. Lesion evaluation and image processing were performed using Segment Medviso software. Mean infarct size and transmurality, measured using RVP‐001, were not different compared with those measured using late gadolinium enhancement images. Bland‐Altman analysis demonstrated a nominal bias of 0.13 mL (<1% of average total lesion volume) for RVP‐001 in terms of gross infarct size measurement. Conclusions The experimental manganese‐based contrast agent RVP‐001 appears to be an effective agent for assessment of myocardial infarction location, size, and transmurality, and it may be useful as an alternative to gadolinium‐based agents.
While many solid tumors are defined by the presence of a particular oncogene, the role that this oncogene plays in driving transformation through the acquisition of aneuploidy and overcoming growth arrest are often not known. Further, although aneuploidy is present in many solid tumors, it is not clear whether it is the cause or effect of malignant transformation. The childhood sarcoma, Alveolar Rhabdomyosarcoma (ARMS), is primarily defined by the t(2;13)(q35;q14) translocation, creating the PAX3-FOXO1 fusion protein. It is unclear what role PAX3-FOXO1 plays in the initial stages of tumor development through the acquisition and persistence of aneuploidy. In this study we demonstrate that PAX3-FOXO1 serves as a driver mutation to initiate a cascade of mRNA and miRNA changes that ultimately reprogram proliferating myoblasts to induce the formation of ARMS. We present evidence that cells containing PAX3-FOXO1 have changes in the expression of mRNA and miRNA essential for maintaining proper chromosome number and structure thereby promoting aneuploidy. Further, we demonstrate that the presence of PAX3-FOXO1 alters the expression of growth factor related mRNA and miRNA, thereby overriding aneuploid-dependent growth arrest. Finally, we present evidence that phosphorylation of PAX3-FOXO1 contributes to these changes. This is one of the first studies describing how an oncogene and post-translational modifications drive the development of a tumor through the acquisition and persistence of aneuploidy. This mechanism has implications for other solid tumors where large-scale genomics studies may elucidate how global alterations contribute to tumor phenotypes allowing the development of much needed multi-faceted tumor-specific therapeutic regimens.
Aortic stenosis (AS) affects about 1.5 million people in the United States and is associated with a 5-year survival rate of 20% if untreated. In these patients, aortic valve replacement is performed to restore adequate hemodynamics and alleviate symptoms. The development of next-generation prosthetic aortic valves seeks to provide enhanced hemodynamic performance, durability, and long-term safety, emphasizing the need for high-fidelity testing platforms for these devices. We propose a soft robotic model that recapitulates patient-specific hemodynamics of AS and secondary ventricular remodeling which we validated against clinical data. The model leverages 3D-printed replicas of each patient’s cardiac anatomy and patient-specific soft robotic sleeves to recreate the patients’ hemodynamics. An aortic sleeve allows mimicry of AS lesions due to degenerative or congenital disease, whereas a left ventricular sleeve recapitulates loss of ventricular compliance and diastolic dysfunction (DD) associated with AS. Through a combination of echocardiographic and catheterization techniques, this system is shown to recreate clinical metrics of AS with greater controllability compared with methods based on image-guided aortic root reconstruction and parameters of cardiac function that rigid systems fail to mimic physiologically. Last, we leverage this model to evaluate the hemodynamic benefit of transcatheter aortic valves in a subset of patients with diverse anatomies, etiologies, and disease states. Through the development of a high-fidelity model of AS and DD, this work demonstrates the use of soft robotics to recreate cardiovascular disease, with potential applications in device development, procedural planning, and outcome prediction in industrial and clinical settings.
Alveolar Rhabdomyosarcoma (ARMS) is primarily defined by the t(2;13)(q35;q14) translocation, which generates the PAX3-FOXO1 oncogene. Despite the fact that ARMS are frequently aneuploid, like a majority of other solid tumors, it is unknown whether PAX3-FOXO1 contributes to the development and/or persistence of aneuploidy. In this study we show that PAX3-FOXO1 serves as the driver mutation to promote aneuploidy by globally altering gene regulatory networks essential for maintaining proper chromosome number and structure. Further, we demonstrate that PAX3-FOXO1 overrides aneuploid-dependent growth arrest by altering the expression of growth factor related regulatory networks. Finally, we present evidence that phosphorylation of PAX3-FOXO1 contributes to these gene regulatory network changes. This is the one of the first studies describing how an oncogene and post-translational modifications of the corresponding oncoprotein drive the acquisition of aneuploidy and override proliferation defects in malignant transformation. The mechanism for PAX3-FOXO1 described in this work has implications for other solid tumors where large-scale genomics studies may elucidate how global alterations contribute to tumor phenotypes allowing the development of much needed multi-faceted tumor-specific therapeutic regimens. Citation Format: Andrew D. Hollenbach, Jacob M. Loupe, Patrick J. Miller, Benjamin P. Bonner, Elaine C. Maggi, Jyothi Vijayaraghavan, Jovanny Zabaleta, Christopher M. Taylor, Fern Miller, Judy S. Crabtree. The PAX3-FOXO1 oncogene drives aneuploidy and overrides aneuploidy-associated proliferative defects in alveolar rhabdomyosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2013.
Purpose The noninvasive measurement of biological tissue elasticity is an evolving technology that enables the robust characterization of soft tissue mechanics for a wide array of biomedical engineering and clinical applications. We propose, design, and implement here a new MRI technique termed asynchronous magnetic resonance elastography (aMRE) that pushes the measurement technology toward a driverless implementation. This technique can be added to clinical MRI scanners without any additional specialized hardware. Theory Asynchronous MRE is founded on the theory of diffuse wavefields and noise correlation previously developed in ultrasound to reconstruct shear wave speeds using seemingly incoherent wavefields. Unlike conventional elastography methods that solve an inverse problem, aMRE directly reconstructs a pixel‐wise mapping of wave speed using the spatial–temporal statistics of the measured wavefield. Methods Incoherent finger tapping served as the wave‐generating source for all aMRE measurements. Asynchronous MRE was performed on a phantom using a Siemens Prismafit as an experimental validation of the theory. It was further performed on thigh muscles as a proof‐of‐concept implementation of in vivo imaging using a Siemens Skyra scanner. Results Numerical and phantom experiments show an accurate reconstruction of wave speeds from seemingly noisy wavefields. The proof‐of‐concept thigh experiments also show that the aMRE protocol can reconstruct a pixel‐wise mapping of wave speeds. Conclusion Asynchronous MRE is shown to accurately reconstruct shear wave speeds in phantom experiments and remains at the proof‐of‐concept stage for in vivo imaging. After further validation and improvements, it has the potential to lower both the technical and monetary barriers of entry to measuring tissue elasticity.
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